Nearly all commonly employed ES cell lines for making genetically modified mice are genotypic male (XY) ES cell lines. As a result, in the F0 generation, all XY animals are male. Most genetic modifications are carried out by targeting the XY ES cells to create a modification of one of two existing alleles, i.e., the donor mouse ES cell is heterozygous for the genetic modification. However, it is often desirable to obtain a mouse that is homozygous for the genetic modification. Because essentially no fully ES cell-derived female mice are born in the F0 generation that comprise the modification, the F0 male is typically bred to a female (e.g., a matched inbred female) to generate a litter in which at least one female (an F1 female) might be heterozygous for the genetic modification. The heterozygous F1 female is then intercrossed with an F1 heterozygous male, to obtain a homozygous progeny. Such breeding requirements represent costly and time-consuming steps. It is desirable to generate a breeding pair in an F0 generation, or at least to generate an F0 female that is largely or fully derived from the donor (XY male) ES cell.
There is a need in the art for methods and compositions for making a fertile female animal in the F0 generation from a donor male (XY) ES cell and a host embryo.